National Resource for Cell Analysis and Modeling Overall Project Summary The National Resource for Cell Analysis and Modeling (NRCAM) develops new technologies for modeling cell biological processes. The technologies are integrated through Virtual Cell (VCell), a problem solving environment built on a central database and disseminated as a client-server application. The philosophy of VCell centers on model reuse, where a physiological model can be repeatedly interrogated and altered to generate predictions from multiple hypotheses and to explore simulations based on different physical or numerical approximations. The VCell model building interface contains abstractions to explicitly support key biophysical mechanisms, including reaction kinetics, diffusion, flow, membrane transport, lateral membrane diffusion, electrophysiology and rule-based models of multi-state/multimolecular interactions. Reaction- diffusion simulations can be based on both 3D analytical and experimental image-based geometries. Users can choose among solvers for: ordinary differential equations, partial differential equations, stochastic reaction kinetics, network-free simulations, spatial stochastic particle kinetics and hybrid spatial stochastic/deterministic simulation. The technology research and development is divided into 4 projects. ?Biology to Physics? focuses on the development of physical formulations for classes of cell biological mechanisms not currently included in VCell. It will develop methods to simulate multi-molecular interactions at a sub-cellular scale for problems where molecular shape and cellular geometry influence the system behavior. ?Physics to Numerics? will develop numerical methods for simulating cell mechanics and reaction- diffusion in domains with moving boundaries; it will also develop improved parallelized solvers for simulations with multiple spatial scales. ?Dynamical Modeling? proposes to address model sharing and reusability as well as the problem of big incompletely constrained models; model construction and visualization will be aided by encapsulating data and mechanisms in reusable ?ModelBricks?; the second aim will develop tools for assessing and optimizing model structure and parameters in the face of sparse data. The overall goal of the TR&D project on ?Spatial Modeling? is a framework for constructing, visualizing and analyzing spatial models and relating them to experimental data, especially models that incorporate kinematics and mechanics. A diverse group of 18 Driving Biological Projects and 28 collaborative projects from outstanding scientists are described. Through a rich repertoire of training, dissemination and outreach activities, NRCAM promotes a quantitative approach to cell biological research.